The Drosophila genes brainiac and egghead have been shown to play essential roles in epithelial development in the embryo and during oogenesis (1-3). Brainiac and egghead encode proteins that are required in the germline to allow for normal interaction between germ-line and somatic cells in the developing ovary (1). In the absence of brainiac or egghead in the germ-line, defects are observed in the overlying follicular epithelium, which is of somatic origin (1;2). On one hand, these follicular epithelial defects resemble defects in EGF receptor signalling between germ-line and follicle cell layers. On the other hand, they resemble a subset of the follicular defects associated with Notch mutants (1;2;4). Defects in female fertility have also been described (5). The diversity of defects caused by brainiac and egghead mutants suggests that they may be involved in communication between cells at a fundamental level and that they can affect multiple signal pathways.
Brainiac and egghead mutants exhibit similar and non-additive phenotypes, leading to the proposal that they function in a common signaling pathway. Signalling pathways are very complex and it may not be possible to predict function of individual genes in such pathways based on genetic studies. For example in a related field, multiple genes were identified based on a common phenotype (Invagination screen) and these genes were later shown to represent many different classes of enzyme activities in different biosynthetic pathways, but all resulting in lack of a particular type of glycoconjugate that preferably was responsible for the phenotype (Hwang H Y, Olson S K, Esko J D, Horvitz H R, Nature. May 22, 2003; 423(6938):439-43).
Based on sequence analysis, Yuan et al. (6) originally proposed that brainiac together with the distant homologous genefringe encoded glycosyltransferases. This hypothesis has subsequently proved correct and both brainiac and fringe represent glycosyltransferases with functionally conserved mammalian homologs (7). Brainiac encodes a UDP-N-acetylglucosamine: βMan β1,3-N-acetylglucosaminyltransferase (β3GlcNAc-T) with a predicted function in biosynthesis of arthroseries glycosphingolipids in the Drosophila. Brainiac was shown to catalyze addition of the third monosaccharide residue to form the trihexosylceramide glycolipid, GlcNAcβ1-3Manβ1-4Glcβ1-Cer. Arthroseries glycolipids have only been found in invertebrates and differ fundamentally from mammalian glycolipids by having a core disaccharide structure based on Manβ1-4Glcβ1-Cer (MacCer) rather than Galβ1-4Glcβ1-Cer (LacCer). Brainiac was shown to transfer β1-3 linked GlcNAc to both MacCer and LacCer, while mammalian homologs only transfer to LacCer (7).